Fluid delivery and measurement systems and methods

ABSTRACT

Fluid delivery and measurement systems and methods are disclosed.

CLAIM OF PRIORITY

This application claims priority under 35 USC §119(e) to U.S.Provisional Patent Application Ser. Nos. 60/250,538 and 60/250,408, bothentitled “Fluid Delivery Systems”; 60/250,295, entitled “Sensor System”;60/250,927, 60/250,422 and 60/250,413, all three entitled “FluidDelivery Systems and Methods”; 60/250,403, entitled “Fluid DeliveryDevice”; all filed on Nov. 30, 2000; and 60/324,412, entitled “FluidDelivery Systems and Methods” and filed on Sep. 24, 2001. The entirecontents of these applications are all hereby incorporated by reference.

FIELD OF THE INVENTION

The invention relates to fluid delivery and measurement systems andmethods.

BACKGROUND

Fluid delivery systems can be used to deliver a fluid, such as apharmacological compound (e.g., a therapeutic agent), from a reservoirto a subject, such as a human. In some embodiments, a fluid deliverysystem includes a housing containing a deformable membrane and a fluidreservoir. The needle is in fluid communication with the fluid reservoirso that as a force is exerted against the deformable membrane, the fluidcan exit the system via the needle. The needle is inserted into asubject (e.g., a human) so that the fluid is injected into the subjectas the fluid leaves the system.

SUMMARY

The invention relates to fluid delivery and measurement systems andmethods.

In one aspect, the invention features a device that includes a housingand a flexible member within the interior of the housing andmechanically coupled to the housing. The flexible member forms first andsecond chambers within the interior of the housing. The device furtherincludes a fluid reservoir within the first chamber of the housing and amicroprobe extending from the fluid reservoir, through the flexiblemember and into the second chamber of the housing.

In some embodiments, the microprobe is configured to move substantiallyfreely in three mutually perpendicular directions. In certainembodiments, the microprobe is configured to translate in a firstdirection and rotate substantially freely in plane perpendicular to thefirst direction

In another aspect, the invention features a device that includes ahousing and a flexible member within the interior of the housing andmechanically coupled to the housing. The flexible member forms first andsecond chambers within the interior of the housing. The device alsoincludes a fluid reservoir within the first chamber of the housing, anda flexible tube having a first end and a second end. The first end ofthe flexible tube is connected to the flexible member and in fluidcommunication with the fluid reservoir via the flexible member. Thedevice also includes a microprobe connected to the second end of theflexible tube. The microprobe can be configured to move substantiallyfreely in three mutually perpendicular directions. The microprobe can beconfigured to translate in a first direction and rotate substantiallyfreely in plane perpendicular to the first direction.

Embodiments can have one or more of the following features.

The first end of the microprobe can be in the fluid reservoir, and thesecond end of the microprobe can be capable of extending to the exteriorof the housing.

The microprobe can be mechanically coupled to the flexible member.

The microprobe can be a needle or a microneedle.

The flexible member can be a septum.

The device can further include a pump in fluid communication with thefluid reservoir. The pump can be configured to draw a fluid from themicroprobe into the fluid reservoir. The pump can be configured todeliver a fluid from the fluid reservoir to the microprobe. The pump canbe a gas generating source. The pump can be an electrochemical cell.

The device can be a device for delivering a fluid from the fluidreservoir to the exterior of the device via the microprobe.

The device can be a device for delivering a fluid to the fluid reservoirfrom the exterior of the device via the microprobe.

The microprobe can be capable of moving a distance in a first directionthat is at least about two percent (e.g., at least about five percent,at least about 10 percent, at least about 20 percent, at least about 30percent, at least about 40 percent, at least about 50 percent, at leastabout 60 percent, at least about 70 percent, at least about 80 percent,at least about 90 percent) of a distance the microprobe is capable ofmoving in a second direction perpendicular to the first direction. Themicroprobe can be capable of moving a distance in a third direction thatis at least about two percent (e.g., at least about five percent, atleast about 10 percent, at least about 20 percent, at least about 30percent, at least about 40 percent, at least about 50 percent, at leastabout 60 percent, at least about 70 percent, at least about 80 percent,at least about 90 percent) of the distance the microprobe is capable ofmoving in the second direction, the third direction being perpendicularto the first and second directions.

In another aspect, the invention features a fluid delivery device thatincludes a first housing and a flexible member within the interior ofthe first housing and mechanically coupled to the first housing. Theflexible member forms first and second chambers within the interior ofthe first housing. The device also includes a gas generator in fluidcommunication with the flexible member via the first chamber of thefirst housing and a microprobe connected to the first housing so thatwhen the gas generator produces a gas pressure sufficient to move themove the flexible member a portion of a fluid disposed in the secondchamber is ejected via the microprobe. The device additionally includesa second housing in fluid communication with the first chamber of thefirst housing so that the second housing is capable of increasing thepressure in the first chamber of the first housing to increase a rate offluid ejection via the microprobe.

In a further aspect, the invention features a fluid delivery device thatincludes a housing and a flexible member within the interior of thehousing and mechanically coupled to the housing. The flexible memberforms first and second chambers within the housing. The device alsoincludes a microprobe connected to the housing and in fluidcommunication with the first chamber of the housing and a gas generatorin fluid communication with the second chamber of the housing. The gasgenerator is capable of increasing the pressure in the second chamber tomove the flexible member thereby ejecting a fluid disposed in the firstchamber out of the housing via the microprobe. The device furtherincludes a current generator in electrical communication with the gasgenerator. The current generator is configured so that when a currentoutput by the current generator is varied, the gas output by the gasgenerator is correspondingly varied and the rate of fluid ejected by themicroprobe is also correspondingly varied.

In one aspect, the invention features a fluid delivery device thatincludes a housing and a flexible member disposed in the interior of thehousing and mechanically coupled to the housing. The flexible memberforms first and second chambers within the housing. A microprobe isconnected to the housing and in fluid communication with the firstchamber of the housing. The device also includes a gas generator influid communication with the second chamber of the housing. The gasgenerator is capable of increasing the pressure in the second chamber tomove the flexible member thereby ejecting a fluid disposed in the firstchamber out of the housing via the microprobe. The device furtherincludes at least one pressure relief valve in fluid communication withthe second chamber of the housing. The pressure relief valve(s) is(are)able to compensate for a difference between a pressure of the interiorof the housing and a pressure of the exterior of the housing.

In another aspect, the invention features a fluid delivery device thatincludes a housing and a flexible member disposed in the interior of thehousing and mechanically coupled to the housing. The flexible memberforms first and second chambers within the housing. A microprobeconnected to the housing and in fluid communication with the firstchamber of the housing, and a gas generator is in fluid communicationwith the second chamber of the housing. The gas generator is capable ofincreasing the pressure in the second chamber to move the flexiblemember thereby ejecting a fluid disposed in the first chamber out of thehousing via the microprobe. The device also includes a second housing, adiluent reservoir in the second housing, a piston in fluid communicationwith the diluent reservoir and a powder chamber in fluid communicationwith the diluent reservoir and the first chamber of the first housing.The piston is configured so that it is capable of applying a pressure tourge a fluid from the diluent reservoir to the powder chamber, therebymixing the fluid with a powder contained in the powder reservoir to forma mixture and to urge the mixture into the first chamber of the firsthousing.

In a further aspect, the invention features a sensor system thatincludes a microprobe, a sensor and a pump. The pump is configured toapply a suction to the microprobe so that the microprobe can withdraw afluid from a body and pass the fluid to the sensor for detection. Thesensor system can further includea flow restriction device between themicroprobe and the sensor along a fluid flow path from the microprobe tothe sensor and a re-fill device in fluid communication between the pumpand the sensor along a fluid flow path from the pump to the sensor.

In one aspect, the invention features a fluid delivery device thatincludes a housing a piston in the interior of the housing, and a gassource in fluid communication with the interior of the housing. Te gassource is configured to exert a pressure against the piston in a firstdirection. The device also includes a resilient device configured toexert a pressure against the piston in a second direction opposite thefirst direction, an arm, an actuation device and a valve having an openposition and a closed position.

In another aspect, the invention features a device that includes a fluidreservoir capable of containing a fluid and a first drive mechanismconfigured to remove a predetermined amount of the fluid from the fluidreservoir when the first drive mechanism is actuated. The device isconfigured to prevent the first drive mechanism from being re-actuateduntil the predetermined amount of the fluid is removed. The device canfurther include a second drive mechanism configured to remove fluid fromthe fluid reservoir at a first predetermined rate. The first drivemechanism can enable fluid to be removed from the fluid reservoir at asecond predetermined rate different than the first predetermined rate.The second predetermined rate can be higher than the first predeterminedrate. The second drive mechanism can be a gas generating source. The gasgenerating source can be in fluid communication with a movable member.The first drive mechanism can be a compressive force. The first drivemechanism can be a spring.

In one aspect, the fluid delivery systems can be designed to provideimproved flexibility and/or patient comfort. For example, the device isdesigned so that a rigid microprobe (e.g., a microneedle or a rigidneedle) can be inserted into a subject (e.g., a human) while the devicemaintains several degrees of freedom so that the subject can move whilefeeling reduced pain because the system responds to the subject'smovement.

In some embodiments, the invention features a device that includes afluid reservoir, a septum, a rigid microprobe (e.g., a needle or amicroneedle), and a housing having an orifice.

Embodiments may include one or more of the following features. Thedevice can have several degrees of freedom of movement. The device canmove relative to a subject. The septum can move, or it can bestationary. The device can include flexible tubing mechanically coupledto the rigid microprobe. The device can be a component of anelectrochemical cell system.

The systems and methods can deliver a fluid to a subject with greatersubject comfort, e.g., with a rigid member, and high reliability.

In another aspect, the invention features systems and methods thatinclude delivering a fluid from a reservoir to a patient at a firstrate, then delivering the fluid from the reservoir to the patient at asecond rate different than the first rate.

In some embodiments, the systems and methods can provide both fluid(e.g., a pharmacological compound, such as a therapeutic agent, such asinsulin) delivery to a patient (e.g., a human) at a relatively constantperiod of time and fluid delivery at an increased rate for a desiredperiod of time. In certain embodiments, this can correspond to a basaldelivery rate and a bolus delivery rate, respectively.

In one embodiment, the invention provides a device that includes adelivery device, an auxiliary gas source and a conduit that providesfluid communication between the delivery device and the auxiliary gassource.

The delivery device can include a gas source, a deformable layer, afluid reservoir and a needle or microneedle in fluid communication withthe fluid reservoir. The components of the delivery device can bearranged so that as the gas source creates a gas within the deliverydevice the created gas exerts a pressure against the deformable layercausing the deformable layer to exert a pressure against the fluidreservoir, causing the fluid in the fluid reservoir to exit the deliverydevice via the needle or the microneedle.

The fluid can be a pharmacological compound (e.g., a therapeutic agent,such as insulin). The gas source in the delivery device can be anelectrochemical cell (e.g., a fuel cell). The auxiliary gas source canhouse a gas mixture at a pressure higher than the pressure of the gas inthe delivery device. The auxiliary gas source can include a gas source.The gas source in the auxiliary gas source can be an electrochemicalcell (e.g., a fuel cell).

In another aspect, the invention features a device that can deliver afluid, such as a therapeutic agent, variably, for example, by varyingthe current output from a current source.

In one embodiment, the invention features a device having a firstchamber, a second chamber, and a deformable membrane between the firstand second chambers. The second chamber includes a variable andcontrollable current source electrically connected to a gas generator.

In another aspect, the invention features systems and methods thatcompensate for a gas pressure differential between an interior andexterior gas pressure to a fluid delivery device.

Compensation can be achieved using one or more valves. For example,compensation can be achieved by having one or more valves open or closeas a result of the gas pressure differential.

The systems and methods can reduce overdelivery and/or underdelivery offluid to a subject (e.g., a human) when the gas pressure differentialbetween the interior and exterior of the delivery device meets orexceeds some predetermined level.

The systems and methods can reduce overdelivery or underdelivery offluid to a subject (e.g., a human) when the gas pressure external to thedelivery device undergoes a relatively rapid decrease or increase,respectively (e.g., when ascending or descending, respectively, in anairplane).

In some embodiments, the invention features a device that includes ahousing, a gas source, a deformable layer, a fluid reservoir, a valve,and a transmission device. The valve can be designed to provide fluidcommunication between the interior and exterior of the housing when thevalve is in a first position, and/or to prevent fluid communicationbetween the interior and exterior of the housing when the valve is in adifferent position. The device can include more than one valve.

The gas source can create a gas that exerts a force against thedeformable layer to cause a fluid contained in the fluid reservoir toexit the device via the transmission device. The gas source can be anelectrochemical cell, such as, for example, a fuel cell. Thetransmission device can be a needle or a microneedle.

In some embodiments, the invention features a device that includes ahousing, a gas source, a piston, a spring, a valve, and an actuationarm.

Embodiments include one or more of the following features. Thecomponents of the device can be assembled so that the gas source canform a gas that exerts a pressure against the piston to move the pistonin a direction away from the gas source. The piston and actuation armcan be mechanically coupled. The spring can be disposed within thehousing so that it exerts a force in a direction opposite to thedirection of the force created when the gas source forms a gas. Theactuation arm can be coupled to a pumping mechanism. The actuation armcan be coupled to a deformable membrane so that the actuation arm canexert a force against the deformable membrane. The deformable membranecan be coupled to a fluid reservoir so that the deformable membrane canexert a force against a fluid contained in the fluid reservoir. Thefluid reservoir can be in fluid communication with a needle or amicroneedle. The actuation arm can exert a force against the deformablemembrane, which can exert a force against a fluid in the fluidreservoir, and the fluid can exit the device via the needle or themicroneedle.

In another aspect, the invention features a device that includes twohousings, the first housing can be used to mix a diluent and a powder toform a mixture, and the second housing can be used to transfer themixture to a subject.

Embodiments include one or more of the following features. The firsthousing can include a diluent chamber and a powder chamber. The diluentand powder chambers can be in fluid communication. The first and secondhousings can be in fluid communication via a seal, which prevents fluidcommunication between the first and second housings until the seal isopened or broken. The second housing can include a reservoir in fluidcommunication with the powder chamber via the seal. The second housingcan further include a gas source and a deformable layer. The secondhousing can further include a transmission device so that fluid can exitthe fluid reservoir via the transmission device.

In another aspect, the invention features a method that includestransferring diluent from a diluent chamber in a first housing to apowder chamber in the first housing to form a mixture, and transferringthe mixture to a fluid reservoir in a different housing.

Embodiments include one or more of the following features. The methodcan further include transferring the mixture from the fluid reservoir toa subject via a transmission device. The methods and devices can includean electrochemical cell (e.g., a fuel cell).

In another aspect, the invention features sensors, such as, for example,pumps that can be used, for example, to detect an analyte (e.g.,glucose) in a patient, as well as systems containing such sensors andmethods. A device, such as an indwelling biosensor, can be used tomonitor certain physiological conditions, such as, for example, theamount and/or concentration of an analyte (e.g., glucose) in a patient'sblood.

In some embodiments, the invention features a system having amicroprobe, a sensor and a pump. The microprobe, sensor and pump are influid communication.

Embodiments include one or more of the following features. The pump canbe an electrochemical cell. The electrochemical cell can be capable ofoperating in a mode that removes oxygen from the system. The microprobecan be in fluid communication with a subject. The devices and methodscan be used to withdraw, to measure and/or to detect a sample, e.g., ananalyte of interest, in a subject without exposing (e.g., withoutdirectly exposing) the sensor to the subject's tissue.

In one aspect, the invention features a fluid delivery system capable ofdelivering a basal dosage (e.g., over about 24 hours) of a fluid, suchas a drug, and/or delivering a bolus dosage of the fluid. A basal dosagecan be, for example, about 0.5 to about 3 units per hour, and a bolusdosage can be, for example, a maximum of 15 units in a maximum time of15 minutes.

In another aspect, the invention features a system and a method capableof delivering a bolus dosage accurately and reliably, for example, withminimized risk of under-dosage or over-dosage. In one embodiment, aftera user starts a first cycle of bolus delivery, a dosage drive mechanismprevents the user from starting a second cycle of bolus delivery untilthe first cycle is completed. For example, the user is prevented fromstarting the second cycle mid-way through the first cycle, which canresult in a one-and-a-half bolus dosage being delivered at the end ofsecond cycle, rather than an intended one bolus dosage. The system andmethod ensure that the first cycle delivers the intended, predetermineddosage without unwanted interruption, thereby allowing the user to knowwhat dosage was delivered, and minimizing the risk of under-dosage orover-dosage.

In certain embodiments, the invention features a method of sensing afluid in a subject. The method includes creating suction in the systemusing an electrochemical cell to withdraw the fluid from the subject.

The devices and methods can provide sample measurement with relativelylow signal loss, relatively little signal drift, and/or relativelylittle calibration loss. The devices and methods can provide relativelyhigh stability (e.g., by not exposing the sensor to a tissueenvironment, such as a tissue environment of the subject). The systemsand methods can use a pump that is relatively small, inexpensive,lightweight, compact and/or inexpensive.

Combinations of embodiments can be used.

Other features, objects, and advantages of the invention will beapparent from the description and drawings, and from the claims.

DESCRIPTION OF DRAWINGS

FIG. 1 is an exploded view of an embodiment of an electrochemical cellsystem.

FIG. 2 is a cross-sectional view of an embodiment of an electrochemicalsystem.

FIG. 3 is a partial perspective view of an embodiment of a fluiddelivery system.

FIG. 4 is a partial perspective view of an embodiment of a fluiddelivery system.

FIG. 5 is a cross-sectional view of an embodiment of a fluid deliverysystem.

FIG. 6 is a cross-sectional view of an embodiment of an auxiliary gassource.

FIG. 7 is a cross-sectional view of an embodiment of an auxiliary gassource.

FIG. 8 is a cross-sectional view of an embodiment of an auxiliary gassource.

FIG. 9 is a cross-sectional, schematic view of an embodiment of a fluiddelivery device.

FIG. 10 is a schematic diagram of a current controller.

FIG. 11 is a schematic diagram of a current controller.

FIG. 12 is a plot of fluid delivery as a function of time.

FIG. 13 is a cross-sectional view of an embodiment of a fluid deliverysystem.

FIG. 14 is a cross-sectional view of an embodiment of an auxiliary gassource.

FIG. 15 is a cross-sectional view of an embodiment of a fluid deliverysystem.

FIG. 16 is a cross-sectional view of an embodiment of a fluid deliverydevice.

FIG. 17 is a schematic representation of an embodiment of a sensorsystem.

FIG. 18 is a schematic representation of an embodiment of a sensorsystem.

FIGS. 19A, 19B, and 19C are graphical representations of the performanceof an embodiment of a sensor.

FIG. 20 is a partial, schematic diagram of an embodiment of a fluiddelivery system.

FIG. 21 is a partial, schematic diagram of an embodiment of a fluiddelivery system.

FIG. 22 is a partial, schematic diagram of an embodiment of a fluiddelivery system.

FIG. 23 is a partial, schematic diagram of an embodiment of a fluiddelivery system.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

The invention relates to fluid delivery and measurement systems andmethods.

FIGS. 1 and 2 show a fluid delivery system 100 used to deliver one ormore fluids such as pharmacological compounds, e.g., one or moretherapeutic agents. System 100 includes a button stopper 102, a button104, a microprobe (e.g., a needle or a microneedle) 106, a spring 108, ashell 110, a bladder 112, a delivery septum 114, a positive batterycontact 116, an electrochemical cell 118, a base 120, a filling septum122, a septum capture ring 124, a negative battery contact 126, abattery 128, a battery spacer 130, a vent 132, a drive volume 134, afluid volume 136, and a delivery path 138. Various features and/orcombinations can be incorporated into system 100 as described herein.

In some embodiments, a force is used to urge fluid from the fluidreservoir, into the microprobe and into a subject (e.g., a human). Incertain embodiments, the force is created using an electrochemical cell,such as a fuel cell. Examples of electrochemical cells are disclosed,for example, in U.S. Pat. Nos. 4,402,817; 4,522,698; 4,902,278; and4,687,423, which are hereby incorporated by reference.

FIG. 3 shows a portion of an embodiment of fluid delivery system 101.System 101 includes a septum 140, a fluid reservoir 142 (e.g.,containing a pharmacological compound), a microprobe 144 (e.g., a rigidmicroprobe, such as a microneedle or a rigid needle) and a housing 146having an orifice 148. In certain embodiments, microprobe 144 can pierceseptum 110 so that microprobe 144 is in fluid communication with fluidreservoir 142. Septum 140, microprobe 144, and housing 146 can move inthe directions indicated by the respective bold arrows (A, B, and C),providing system 101 to have these degrees of freedom.

FIG. 4 shows a portion of a delivery system 150 in which a flexibleportion 152 (e.g., a flexible tubing) connects microprobe 144 with aseptum 154. Septum 154 is stationary, but housing 146 and microprobe 144can move as indicated by the respective bold arrows (X and Y), providingsystem 150 with these degrees of freedom.

In certain embodiments, housing 146 can further include a breakablemembrane, such as a polymeric membrane, extending across orifice 148.The membrane can be connected to microprobe 144 to hold the microprobein place, e.g., centered in orifice 148, during packing and storage ofsystem 100. When system 100 is applied to a subject, this causesmicroprobe 144 to move, e.g., upward, thereby pulling the membrane fromorifice 148 and allowing the microprobe to move with multiple degrees offreedom.

Under certain circumstances, it can be desirable for a fluid deliverysystem to deliver fluid to the subject at a relatively constant rate.Under some circumstances, however, it can be desirable for the system todeliver (at least for a period of time) fluid to the subject at arelatively high rate.

FIG. 5 shows a system 160 including a fluid delivery device 162 and anauxiliary gas source 164. Fluid delivery device 162 includes a transportdevice (e.g., a microprobe or a microneedle or a needle) 166, adeformable layer (e.g., a deformable membrane) 168, a fluid reservoir(e.g., a reservoir containing pharmacological compound) 170, and a gassource 172. Fluid delivery device 162 is connected to auxiliary gassource 164 via conduit 174 that includes valve 176.

Under certain circumstances when it is desirable for delivery device 160to deliver fluid to the subject via device 162 at a relatively constantrate, valve 176 is generally closed so that device 160 and auxiliary gassource 164 are not in fluid communication. When valve 174 is closed,fluid delivery device 162 delivers fluid from reservoir 168 to thesubject via device 162 as follows. Gas source 172 forms a gas insidedevice 162 between gas source 172 and layer 168. As the amount of gasformed by source 172 increases, layer 168 is deformed and exerts apressure against fluid in reservoir 170, thereby forcing the fluidthrough device 166. Gas source 172 can be, for example, anelectrochemical cell, such as a fuel cell that generates oxygen indevice 110, as described above.

Under circumstances when it is desirable to deliver (at least for aperiod of time) fluid to the subject via device 166 at a relatively highrate, the pressure of gas in auxiliary gas source 164 is held at and/orincreased to a pressure higher than the gas pressure in device 162.Valve 176 is then opened, allowing gas to flow from source 164 intodevice 162 via conduit 174. This increases the pressure exerted on layer168, thereby increasing the rate at which fluid is delivered fromreservoir 170 to the subject via device 166.

Auxiliary gas source 164 can be a body of gas held at a relatively highpressure. Alternatively or additionally, gas source 164 can include apiston 178 that is depressed in conjunction with the opening of valve176 and a portion 180 that moves as piston 178 is depressed (FIG. 6).FIG. 7 shows another embodiment in which auxiliary gas source 164includes a gas source 182 that generates a gas within the auxiliary gassource, such as described above with respect to device 162. For example,gas source 182 can be an electrochemical cell as described above. Incertain embodiments, auxiliary gas source 164 can provide an increasedpressure via chemical reactions (e.g., relatively rapid chemicalreactions) that occur within the auxiliary gas source (e.g., reactionsbetween vinegar and sodium bicarbonate). The gases created can bedirectly added into device 162, or an increased pressure can be achievedin device 162 by allowing the gases created in the chemical reactions topush, for example, a syringe plunger 184 that increases the gas indevice 162 (FIG. 8).

In some embodiments, the gas pressure can be held at a relatively highvalue in auxiliary gas source 164. In certain embodiments, the gaspressure in auxiliary gas source 164 is increased just prior to, or atthe same time as, valve 176 is opened.

Valve 176 may be manually opened as desired. Valve 176 may be opened atpredetermined intervals. Valve 176 may be opened based upon the value ofsome parameter (e.g., the concentration of an analyte, such as glucose,in a patient).

Alternatively or in addition, in some embodiments, it is desirable for afluid delivery system to deliver a fluid at a predetermined rate, e.g.,a variable rate of delivery.

FIG. 9 shows a fluid delivery device 190 that includes a housing 192 anda deformable member (e.g., a deformable membrane) 194 inside thehousing. Housing 192 and member 194 define a first chamber 196 and asecond chamber 198. Device 190 includes a microprobe 199, such as aneedle or a microneedle, having a lumen in fluid communication withfirst chamber 196 and an environment outside housing 192.

First chamber 196 includes a pharmacological compound 200, such as a,e.g., insulin.

Second chamber 198 includes a button 202, a current generator 204, e.g.,a DC current generator, in electrical communication with the button, anda gas generator 206 in electrical communication with the generator. Gasgenerator 206 is generally as described above. When a user pressesbutton 202, this activates generator 204, which in turn sends a currentto gas generator 206 to create a gas (e.g., oxygen gas) in secondchamber 198. As gas is generated, pressure in second chamber 198increases, which exerts a force on membrane 194 (e.g., pushes membranetoward microprobe 199). This, in turn, pushes compound 200 out throughthe lumen of microprobe 199 to, for example, a subject.

In some embodiments, the rate at which compound 200 is delivered throughmicroprobe 199 is controlled by controlling the amount of current thatgenerator 204 produces. This, in turn, controls the amount of gasgenerated by gas generator 206, the amount of pressure created in secondchamber 198, and the amount of force exerted on membrane 194. Forexample, an increase in current output from current generator 204increases compound delivery; and a decrease in current output decreasescompound delivery.

The current from current generator 204 can be controlled or altered byusing a standard current generator having a selector switch configuredto alter the resistance in the circuitry of the generator. Current canbe increased by switching to a low resistance resistor, and current canbe decreased by switching to a high resistance resistor. FIGS. 10 and 11show a FET and LM334 current controller, respectively, that can be usedto control current by changing resistors. With these current generatorsystems, the active device can regulate current even with decay in thevoltage of the battery.

In some embodiments, the current control generator or system can becombined with a software system, e.g., one having a microprocessor, forremote control by the user. Accordingly, a variety of configurations canbe implemented depending on the clinical need of the patient and theproperties of a therapeutic agent. For example, the therapeutic agentcan be delivered according to a circadian schedule, such as high dosagewhen the patient is asleep. Thus, this system permits an “electronicformulation” or adjustment of therapeutic agent dosage or delivery overthe period of ambulation in a delivery system that can, for example, bedisposable.

FIG. 12 is a plot of fluid, e.g., a therapeutic agent, delivery (inunits per hour) as a function of time. FIG. 12 shows that the amount offluid delivery can be controllably varied at least over 24 hours byvarying the applied current to current generator 204. For example, from10-12 pm, a constant current (CC) of about 1,070 microamps was applied,which delivered about 30 units per hour. When the current was reduced toabout 167 microamps, the rate of delivery decreased to about 3-4 unitsper hour. Then, the rate of delivery can be increased again byincreasing the current. The current output from generator 204 can becontrolled by a variety of ways, including using constant current and/orusing constant voltage.

Under certain circumstances, there can be a relatively rapid change inthe ambient gas pressure external to a fluid delivery system (e.g.,during ascent or descent of an airplane). This can result in a change inthe rate of deliver of the fluid to the subject.

FIG. 13 shows a fluid delivery system 210 including a housing 212, a gassource 214, a deformable layer 216, a transmission device (e.g., amicroprobe, a microneedle or a needle) 218, a fluid reservoir 220containing a fluid, and a valve 222. System 210 delivers fluid fromreservoir 220 to a subject when valve 222 is closed and gas source 214forms a gas inside housing 212 between the gas source and layer 216. Asthe amount of gas formed by source 214 increases, layer 216 is deformedand exerts a pressure against fluid in reservoir 220, thereby forcingthe fluid through device 218. In certain embodiments, the gas pressureinside housing 212 between gas source 214 and layer 216 can be slightlyhigher than the ambient gas pressure external to system 210.

Without wishing to be bound by theory, it is believed that the change indelivery rate that is due to the change in the gas pressure differentialbetween the ambient gas pressure external to system 210 and the gaspressure inside housing 212 between gas source 214 and layer 216. Forexample, assuming an ideal gas forms the ambient environment external tosystem 210 and an ideal gas forms the gas pressure inside housing 212between gas source 214 and layer 216, a change in the ambient gaspressure from 14.7 pounds per square inch (approximate ambient gaspressure at sea level) to 10 pounds per square inch (approximate ambientgas pressure at 15,000 feet), can correspond to an almost 50% increasein the gas volume. This can result in overdelivery of the fluid fromreservoir 220 to the subject. Similarly, underdelivery of the fluid fromreservoir 220 to the subject can occur as the ambient gas pressureexternal to system 210 undergoes a relatively rapid decrease (e.g., whena plane descends).

Accordingly, valve 222 is designed to open to assist in decreasing a gaspressure differential between the ambient gas pressure external tosystem 210 and the gas pressure inside housing 212 between gas source214 and layer 216. For example, valve 222 can be a bi-directional valvedesigned so that when this gas pressure differential meets or exceedssome predetermined value the valve allows gas to flow from therelatively high gas pressure environment to the relatively low gaspressure environment, thereby assisting in decreasing the gas pressuredifferential. Such valves are commercially available from, for example,Vernay.

FIG. 14 shows a fluid delivery system 230 that contains valves 232 and234, each of which is a one-way valve (e.g., a “pop-off” valve, a“mushroom-capped” valve). Valves 232 and 234 are designed so that, ifthe ambient external gas pressure to system 210 exceeds the gas pressureinside housing 212 between gas source 214 and layer 216 by somepredetermined value, valve 232 opens so that the gas pressuredifferential decreases. Valves 232 and 234 are also designed so that, ifthe gas pressure inside housing 212 between gas source 214 and layer 216exceeds the ambient external gas pressure to system 210 by somepredetermined value, valve 234 opens so that the gas pressuredifferential decreases.

Various combinations of pressure relief valves can be used. Generally,the combination(s) of relief valve(s) is designed to reduce the gaspressure differential between the internal and external gas pressures ofthe delivery system when the gas pressure differential meets or exceedssome predetermined value.

In certain embodiments, the internal pressure differential at which thedevice works to provide a desired fluid flow can be relatively low(e.g., about 0.2 PSIG or less). In some embodiments, one or morecomponents can be included in the device to provide a resistive force toincrease the internal pressure differential at which the device works toprovide the desired fluid flow. For example, a spring can be disposedbeneath the flexible member. This can, for example, decrease theabsolute and/or relative pressure differential used for pressure reliefvalve(s) to operate relative the internal pressure differential used toprovide desired fluid flow for the device, thereby enhancing the overallsensitivity of the device to changes in the internal/external pressuredifferential (e.g., due to a change in altitude).

Other embodiments for minimizing overdelivery and/or underdelivery arepossible. FIG. 15 shows a fluid delivery system 240 including a housing242, a gas source 244, a resilient device 246 (e.g., a spring), an arm248 (e.g., a drive arm, a cam, a linkage, a ratchet device), a piston250, seals 252 and 254 (e.g., O-rings), an actuation device 256 (e.g., avalve actuation arm), and a valve 258. Arm 248 is in mechanicallycoupled to a pumping mechanism 260 (e.g., a deformable layer) thatdelivers a fluid to a patient via a transmission device, such as amicroprobe, a microneedle or a needle.

When valve 258 is closed, gas source 244 forms a gas, which urges piston250 against device 246 and which moves arm 248 away from source 244.When the piston reaches a position at a predetermined distance from gassource 244, device 256 causes valve 258 to open, decreasing the gaspressure differential between the interior of housing 242 and theexterior of the housing. Alternatively, the position of valve 258 (e.g.,open or closed) can be selected manually, or can be determined basedupon some measured parameter (e.g., the differential between the gaspressure inside housing 242 and the gas pressure outside the housing).

The rate at which piston 250 moves distally from gas source 244 candepend upon the differential between the gas pressure inside housing 242and the gas pressure outside the housing. For example, the amount oftime it takes for piston 250 to move a given distance away from gassource 244 can vary proportionally with the variation in thedifferential in the gas pressure inside housing 242 and the gas pressureoutside the housing (e.g., if at a given gas pressure differential ittakes piston 250 one second to move a given distance from gas source244, then at half that gas pressure differential, it will take pistontwice as long to move that distance from the gas source).

In some embodiments, the piston and seals assembly can be replaced witha bellows sealed to the gas source. In certain embodiments, thecircuitry of the gas source can be connected to flip/flop polarity sothat it switches, for example, from oxygen generation mode to oxygenremoval mode. The polarity can be reversed by, for example, a timedresponse, a mechanical limit switch, or both. In these embodiments, thesystem can be designed to not include the return spring or valveactuation arm, and the valve could be replaced with valves describedabove.

Referring to FIG. 20, a fluid delivery system 10 includes base 11positioned thereon, a fluid housing 12, a needle or microneedle housing14, and a movement system 16 for moving the fluid housing. Fluid housing12, e.g., a glass cylinder vial, contains a fluid 18 (e.g., apharmacological compound, such as a drug) between a sealed end 20 and anopen end 22 sealed with a pierceable member 24, such as a rubber stopperor septum. Member 24 provides fluid housing 12 with a fluid-tight sealso that fluid 18 does not leak from the housing, but member 24 andhousing 14 can slide within the housing. That is, fluid housing 12 isconfigured to slidably receive member 24 and housing 14, as describedbelow. Housing 14, which includes a double-pointed needle 26, is fixedlyattached to base 11. Examples of housings, including a needle or amicroneedle, are described herein.

Movement system 16 includes a gear rack 28, a pinion gear 30, a spurgear 32, and a pawl 34. Gear rack 28 has two projections 36 that engage,e.g., hold, ends 20 and 22 of fluid housing 12 to couple the fluidhousing to the gear rack. Gear rack 28 further includes teeth 38 thatengage pinion gear 30, and the pinion gear is rotatably connected tospur gear 32. The gear ratios of gear rack 28, pinion gear 30 and spurgear 32 are selected to provide a predetermined amount of movement ofthe gear rack in response to a predetermined movement of the spur gear,e.g., sufficient for drug delivery. Pawl 34 is attached to base 11 atone end and engages with the teeth of spur gear 32 at the other end.Pawl 34 serves as an anti-reverse mechanism that allows spur gear 32 torotate in only one direction, here clockwise (arrow A). Pawl 34 alsomaintains a load on fluid housing 12 as a drive mechanism (describebelow) is reset.

During use, fluid 18 is delivered from fluid housing 12 through needleor microneedle 26 by translating fluid housing 12 toward housing 14(arrow B). Spur gear 32 is rotated clockwise, which rotates pinion gear30 clockwise. Pawl 34 prevents spur gear 32 from rotatingcounter-clockwise. As pinion gear 30 rotates, its teeth engage withteeth 38 of gear rack 28, which translates the gear rack in thedirection of arrow B. Since gear rack 28 is coupled to fluid housing 12by projections 36, the fluid housing is also translated in the direct ofarrow B toward housing 14. As fluid housing 12 is moved toward housing14, one end of needle or microneedle 26 pierces through member 24, andthe other end of the needle or microneedle pierces a subject, e.g., ahuman. Fluid 18 is delivered through needle or microneedle 26 bycontinuing to move fluid housing 12 toward housing 14 with member 24sliding inside the fluid housing, e.g., like a piston. In someembodiments, it is preferable that needle or microneedle 26 piercesmember 24, and fluid 18, e.g., a drop or less, flows entirely throughthe needle or the microneedle before the needle or the microneedlepierces the subject. This can prevent or minimize contamination of fluid18, e.g., if the needle or the microneedle pierces the subject first andthe subject's bodily fluid can enter fluid housing 12.

FIG. 21 shows an embodiment of fluid delivery system 10 having a drivemechanism 40 capable of delivering a basal dosage of fluid 18. Mechanism40 includes an inlet port 42, a piston system 44, and a driver 46. Port42 is interfaced with a gas-generating source (not shown) such as anelectrochemical cell, e.g., an electrolytic cell. Gas-generating sourcesare disclosed in U.S. Pat. Nos. 4,402,817; 4,522,698; 4,902,278; and4,687,423. Gas from the gas source is provided to drive piston system44, which includes a piston 48 and an exhaust port 50. Piston 48 sconnected to a torsion spring 49 configured to force the piston towardinlet port 42. Piston 48 is also connected to driver 46 and linked toexhaust port 50, e.g., a valve, by a linkage 52. Driver 46 is configuredto engage with spur gear 32 such that as piston 48 moves away from inletport 42, the driver can rotate the spur gear, e.g., clockwise. Linkage52 is provided to open exhaust port 50 when piston 48 reaches apredetermined position along its upstroke, e.g., at the end of itsstroke, and triggers the linkage. Opening exhaust port 50 vents gas inpiston system 44 so that spring 49 can force piston 48 back to aninitial stroke position, e.g., adjacent to port 42. After gas is ventedfrom piston system 44 and piston 48 completes its downstroke, linkage 52closes exhaust port 50.

During use, gas is continuously introduced via port 42 into pistonsystem 44. With piston 48 at the initial stroke position and port 50closed, as the gas pressure increases in system 44 and overcomes theforce of spring 49, the gas advances the piston and driver 46 towardspur gear 32, thereby rotating the spur gear. As described above,rotation of spur gear 32 delivers fluid 18 through needle or microneedle26. Piston 48 continues to advance until it reaches a predeterminedposition where it causes linkage 52 to open exhaust port 50. Openingport 50 vents gas in system 44, and allows spring 49 to force piston 48to its initial stroke position (and retracts driver 46), where linkage52 now closes the exhaust port. Since gas is continuously introducedinto piston system 44, the stroke cycle of piston 48 and driver 46 isrepeated, thereby continuing to deliver fluid 18 through needle ormicroneedle 26.

FIG. 22 shows an embodiment of fluid delivery system 10 having a drivemechanism 54 capable of delivering a bolus dosage of fluid 18. Mechanism54 is shown in an untriggered condition. Mechanism 54 includes a shaft56, a button release lever 58, and a button lock-up bar 60.

Shaft 56 includes positioned thereon a button 62, a button extensionspring 64, a bolus actuator 66, and a bolus drive spring 68. Button 62and actuator 66 are slidably positioned on shaft 56. Button 62 is asquare, hollow member having a notch 70. Springs 64 and 68 arepositioned on shaft 56 such that they can be compressed and extended onthe shaft when button 62 and actuator 66 are moved along the shaft.Actuator 66 is also a square, hollow member that includes an actuatortab 72, e.g., spring steel, that can engage with the teeth of spur gear32 to rotate the spur gear, e.g., drive the gear in the direction ofarrow A. Shaft 56 is connected to base 11 on one end.

Button release lever 58 is pivotally connected to base 11 at connection74. Lever 58 is biased in the direction of arrow C by a lever spring 76.Lever includes a portion 88 that can engage with notch 70.

Button lock-up bar 60 is also pivotally connected to base 11, atconnection 78. Button lock-up bar 60 is biased in the direction of arrowD by a spring (not shown). Button lock-up bar 60 includes an edge 80that is chamfered, e.g., at about 45°, and that contacts an end 82 ofbolus actuator 66 when mechanism 54 is in an untriggered condition.Lock-up bar 60 further includes an end 84 that can engage with an end 86of button 62.

As shown in FIG. 22, in an untriggered condition, button release lever58 is spring-biased in the direction of arrow C, and button lock-up bar60 is spring-biased in the direction of arrow D. Springs 64 and 68 areextended.

During use, for example, when a user wants to deliver a bolus dose offluid 18, the user first depresses button 62 (shown extended in FIG. 22)in the direction of arrow E along shaft 56 until notch 70 engages withportion 88 of button release lever 58. Portion 88 locks button 62 in adepressed position. Depressing button 62 also compresses springs 64 and68 along shaft 56 and moves bolus actuator 66 and tab 72 in thedirection of arrow E. Tab 72 deflects as it travels over the teeth ofspur gear 32. Since lock-up bar 60 is biased in the direction of arrowD, and bolus actuator 66 has been moved out of contact with edge 80 bydepressing button 62, the lock-up bar rotates (arrow D) about connection78, and end 84 rotates to contact the side of the button. With button 62depressed and locked, drive mechanism 54 is in a “cocked” condition.

To trigger drive mechanism 54, the user rotates button release lever 58about connection 74 in the direction opposite arrow C, here clockwise.This releases the locking engagement between notch 70 and portion 88,and allows button 62 to be returned to its untriggered position by thespring force of spring 64. Similarly, bolus actuator 66 is returned toits untriggered position by the controlled and predetermined springforce of spring 68. As bolus actuator 66 returns (in the directionopposite arrow E) actuator tab 72 engages spur gear 32 at a controlledforce and rotates the spur gear, thereby delivering a bolus dose at acontrolled rate. When bolus actuator 66 returns to its untriggeredposition, edge 82 contacts edge 80 to rotate lock-up bar 60 in thedirection opposite arrow D, thereby moving end 84 away from end 86 andallowing button 62 to be depressed. Before bolus actuator 66 is returnedto its untriggered position, however, lock-up bar 60 is biased in thedirection of arrow D (upwardly as shown in FIG. 22), such that, if theuser tried to depress button 62, end 84 would butt against end 86 andprevent the button from being depressed. This mechanism prevents theuser from re-cocking and re-triggering the bolus delivery mechanismbefore the bolus dosage is completed. As a result, the risk that a usercan deliver an unwanted bolus dosage—over-dosage or under-dosage—isminimized. Each trigger of drive mechanism 54 can provide apredetermined bolus dosage at a controlled rate, so the risk ofunder-dosage is minimized. The user is prevented from re-triggering thedrive mechanism until the predetermined dosage is delivered, so the riskof over-dosage is minimized.

While drive mechanisms 40 and 54 are described above separately, incertain embodiments, the drive mechanisms are integrated in a fluiddelivery system such that the delivery system can deliver a basal dosageand a bolus dosage on demand.

While certain embodiments have been disclosed, the invention is notlimited in this sense. For example, FIG. 23 shows an embodiment of apiston system 1100 that can be used in drive mechanism 40 describedabove. System 1100 includes a piston assembly 1102, a linkage assembly1104, and a valve 1106, e.g., a T-shape valve. Piston assembly 1102includes a piston 1108, a piston housing 1110, and a spring 1111. Spring1111 is configured to bias piston 1108, e.g., with linear force, in thedirection of arrow F, for example, to bias the piston to a positionadjacent to valve 1106. In some embodiments, piston 1108 is connected todriver 46 in the drive mechanism described above to delivery fluid 18.Piston assembly 1102 further includes a gas inlet 1113 that is in fluidcommunication with the interior of housing 1110 and a gas source (notshown), such as an electrochemical cell described above.

Linkage assembly 1104 includes a first lever arm 1112, a linkage bar1114, and a second lever arm 1116. First lever arm 1112 is connected tolinkage bar 1114 by a freely pivoting connection; and the linkage bar isconnected to second lever arm 1116 by a slotted connection 1118 and tovalve 1106. First lever arm 1112 is further engaged to a ball plunger1120 via a first detent 1124 or a second detent 1126 on the first leverarm. At one end, ball plunger 1120 includes a ball 1122 that can rest infirst detent 1124 or second detent 1126. At the other end, plunger 1120is fixedly connected, for example, to a housing of system 1100 via aspring or a rigid connection. Linkage assembly 1104 is connected topiston 1108 at one end of first lever arm 1112, for example, by a springor a rigid connection such as a rod.

In operation, piston 1108 is at an initial position, e.g., adjacent tovalve 1106. Linkage assembly 1104 is configured such that the pivotingand lever action of lever arms 1112 and 1116 and linkage bar 1114 causesthe valve to be closed. Piston housing 1110 is sealed. Ball 1122 is atrest in first detent 1124.

As gas is continuously introduced via inlet 1113 into housing 1110, thegas pressure inside the housing 1110 increases and overcomes the springforce of spring 1111. Piston 1108 is moved away from valve 1106. Themovement of piston 1108 can be used to drive driver 46 to deliver afluid.

When piston 1108 reaches a predetermined position, e.g., at the end ofits upstroke, the piston pushes on first lever arm 1112 such that ball1122 is displaced from first detent 1124 to second detent 1126. Thisaction causes linkage assembly 104 (by pivoting and lever action) toopen valve 1106. Opening valve 1106 vents gas from piston housing 1110,and the spring force of spring 1111 causes piston 1108 to return to itsinitial position. As piston 1108 travels back to its initial position,ball 1122 is still in second detent 1126, thereby ensuring that valve1106 stays open until the piston returns to a predetermined position,e.g., its initial position, i.e., for the entire return stroke. Forexample, if valve 1106 were just “cracked” or closed during the returndownstroke, piston 1108 could be stalled midway through the entirestroke cycle. When piston 1108 reaches its initial position, the pistonpushes and closes valve 1106, and the mechanical action of linkageassembly 1104 displaces ball 1122 from second detent 1126 to firstdetent 1124. The stroke cycle of the piston is repeated as gas isintroduced into housing 1110.

Thus, system 1100 is generally configured to ensure that piston 1108completes its stroke cycle, e.g., from an initial position to a finalposition and back to the initial position, without restarting its cycleduring the cycle. When coupled, for example, to a fluid delivery system,system 1100 can provide an accurate and reliable drive mechanism.

FIG. 16 shows a system 270 that includes a first chamber 272 and asecond chamber 274. Chamber 272 contains a diluent reservoir 276 coupledto a button 278 via a piston 280 so that when the button is depressed,the piston moves in the direction shown by the arrows. This causes thediluent to move along a path 282 and enter a powder chamber 284, whichcontains a dried powder, such as, for example, a pharmacologicalcompound (e.g., a lyophilized therapeutic agent). When the diluententers chamber 284, the dried powder is reconstituted. The reconstitutedmixture (e.g., therapeutic agent/diluent mixture) can move along a path286 to a seal 288. Seal 288 can be, for example, a sterility seal. Ifseal 288 is broken (e.g., by being sheared as system 270 is mounted on,for example, a subject), then the reconstituted mixture can pass into areservoir 290 contained in chamber 274. Chamber 274 also includes a gassource 292 as described above, a deformable layer 294, and atransmission device 296 (e.g., a needle or a microneedle).

When gas source 292 is activated (e.g., by the user pressing a button),the gas source creates a gas in housing 274 between the gas source anddeformable layer 294. This exerts a force on deformable layer 294,which, in turn, causes fluid (e.g., a fluid and the therapeuticagent/diluent mixture) in reservoir 290 to exit housing 274 via device296. In some embodiments, the fluid is transferred into a subject (e.g.,a human) (e.g., when device 296 is inserted into the subject).

In certain embodiments, the user can press a button that activates(e.g., simultaneously activates) both the electrochemical cell andcauses the transmission device to be inserted into the subject so that afluid path is connected between the fluid reservoir and the subject. Insome embodiments, such as when it is desirable to have a long stroke onthe button, the actions can be performed sequentially using detents orpartial mechanical stops during travel of the button.

In some embodiments, a fluid delivery system can be adapted for use as asensor.

FIG. 17 shows an embodiment of a sensor system 300 including amicroprobe 302, a sensor 304, a pump 306 and a subject (e.g., a human)308. Microprobe 302 is in fluid communication with sensor 304 via afluid path (e.g., tubing) 310, and the sensor is in fluid communicationwith pump 306 via a fluid path (e.g., tubing) 312.

During use of system 300, pump 306 creates a suction or partial vacuumthat can remove a sample (e.g., a fluid sample, such as a blood sample)from subject 308. The sample passes through microprobe 302 (e.g., aneedle or a microneedle) and along path 310 to sensor 304 (e.g., a bloodglucose sensor), where one or more species of interest (e.g., analytesof interest, such as glucose) is measured. The sample then moves alongpath 312 to pump 306 and exits system 300 via an exhaust 314 (e.g., agas exhaust) and/or exhaust 316 (e.g., a waste exhaust). Exhaust 314and/or 316 can be in fluid communication with, for example, a disposablebag.

In some embodiments, pump 306 is an electrochemical cell that operatesin reverse mode so that it removes oxygen present between microprobe 302and sensor 304 (e.g., in microprobe 302, path 310, the sensor, path 312and/or the pump) and exhausts via exhaust 314. By using up this oxygen,pump 306 reduces the pressure between microprobe 302 and sensor 304,thereby creating suction or a partial vacuum and allowing the sample tobe removed from subject 308. Because there is only about 20% oxygen inair, the suction created by the electrochemical cell can be limited. Anexample of an electrochemical cell is a symmetrical Pt/NAFION® fuelcell. Examples of electrochemical cells are described above.

FIG. 18 shows an embodiment of a sensor system 320 that includes a flowrestriction device (e.g., a valve clamp) 322 and a re-fill device (e.g.,a re-fill valve) 324.

During use of system 320, pump 306 creates a suction or partial vacuumthat can remove a sample (e.g., a fluid sample, such as a blood sample)from subject 308. The sample passes through microprobe 302 and along apath 326 (e.g., tubing) to flow restriction device 322. The sample thenpasses along a path 328 (e.g., tubing) to sensor 304. The sample thenpasses along a path 330 (e.g., tubing) to re-fill device 324. The samplethen passes along a path (e.g., tubing) 332 to pump 306, and then out ofsystem 320 via exhaust 314 and/or 316.

Device 324 can be used to periodically (e.g., at predetermined and/ortimed intervals, and/or at intervals determined in response to a signal,such as a measurement of the amount of oxygen in fluid communicationwith path 330, path 332 and/or device 324) re-fill air into system 320,thereby allowing continuous or semi-continuous extraction of fluid fromsubject 308 via microprobe 302. When device 324 is opened to re-fill airinto system 320, device 322 can be closed to prevent fluid communicationbetween subject 304 and sensor 304.

FIG. 19A shows an embodiment of oxygen values as a function of time forsystem 320. FIGS. 19B and 19C show the corresponding values of theposition (i.e., open/closed) of devices 322 and 324, respectively, as afunction of time for system 320.

In other embodiments, more than one electrochemical cell can be used toprovide suction in an alternating pattern to provide continuous orsemi-continuous extraction of fluid from subject 308.

Pump 306 can be placed in various positions so long as it is capable offorming suction or a partial vacuum as discussed above. For example, insome embodiments, pump 306 is between microprobe 302 and sensor 304.

Combinations of embodiments can be used.

Therapeutic agents that can be used in the devices and methods describedherein include, for example, vaccines, chemotherapy agents, pain reliefagents, dialysis-related agents, blood thinning agents, and compounds(e.g., monoclonal compounds) that can be targeted to carry compoundsthat can kill cancer cells. Examples of such agents include, insulin,heparin, morphine, interferon, EPO, vaccines towards tumors, andvaccines towards infectious diseases.

The device can be used to deliver a therapeutic agent to any primate,including human and non-human primates. The device can be used todeliver an agent, e.g., a therapeutic agent to an animal, e.g., a farmanimal (such as a horse, cow, sheep, goat, or pig), to a laboratoryanimal (such as a mouse, rat, guinea pig or other rodent), or to adomesticated animal (such as a dog or cat). The animal to which thetherapeutic agent is being delivered can have any ailment (e.g., canceror diabetes). It is expected that the device may be most useful intreating chronic conditions. However, the device can also be used todeliver a therapeutic agent (such as a vaccine) to an animal that is notsuffering from an ailment (or that is suffering from an ailmentunrelated to that associated with the therapeutic agent). That is, thedevice can be used to deliver therapeutic agents prophylactically.

The devices and methods of the invention can be used to individuallytailor the dosage of a therapeutic agent to a patient.

The devices and methods of the invention can allow for outpatienttreatment with increased convenience, such as, for example, without theuse of an I.V.

Devices and methods described herein can be advantageous because theycan be used to promote maintenance of the concentration of a therapeuticagent in a patient's plasma within a safe and effective range. Moreover,the device can release therapeutic agents in response to theconcentration of an analyte in the patient's system. Thus, the rate ofdrug delivery can be appropriate for the patient's physiological stateas it changes, e.g., from moment to moment.

Other embodiments are within the claims.

1. A device, comprising: (1) a housing having an interior and anexterior; (2) a flexible member within the interior of the housing andmechanically coupled to the housing, the flexible member forming firstand second chambers within the interior of the housing; (3) a fluidreservoir within the first chamber of the housing; and, (4) a microprobeextending from the fluid reservoir, through the flexible member and intothe second chamber of the housing, the microprobe being configured tomove substantially freely in three mutually perpendicular directions. 2.The device of claim 1, wherein a first end of the microprobe is in thefluid reservoir and a second end of the microprobe is capable ofextending to the exterior of the housing.
 3. The device of claim 1,wherein the microprobe is mechanically coupled to the flexible member.4. The device of claim 1, wherein the microprobe comprises a needle. 5.The device of claim 1, wherein the microprobe comprises a microneedle.6. The device of claim 1, wherein the flexible member comprises aseptum.
 7. The device of claim 1, further comprising a pump in fluidcommunication with the fluid reservoir.
 8. The device of claim 7,wherein the pump is configured to draw a fluid from the microprobe intothe fluid reservoir.
 9. The device of claim 7, wherein the pump isconfigured to deliver a fluid from the fluid reservoir to themicroprobe.
 10. The device of claim 9, wherein the pump comprises a gasgenerating source.
 11. The device of claim 9, wherein the pump comprisesan electrochemical cell.
 12. The device of claim 7, wherein the pumpcomprises a gas generating source.
 13. The device of claim 7, whereinthe pump comprises an electrochemical cell.
 14. The device of claim 1,wherein the device comprises a second device for delivering a fluid fromthe fluid reservoir to the exterior of the device via the microprobe.15. The device of claim 1, wherein the device comprises a second devicefor delivering a fluid to the fluid reservoir from the exterior of thedevice via the microprobe.
 16. The device of claim 1, wherein themicroprobe is capable of moving a distance in a first direction that isat least about two percent of a distance the microprobe is capable ofmoving in a second direction perpendicular to the first direction. 17.The device of claim 16, wherein the microprobe is capable of moving adistance in a third direction that is at least about two percent of thedistance the microprobe is capable of moving in the second direction,the third direction being perpendicular to the first and seconddirections.